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The efficacy of pegylated interferons in the treatment of chronic hepatitis B has shown superior results to standard of care in patients only infected with hepatitis B. The efficacy of pegylated interferon for the treatment of chronic hepatitis B in HIV-coinfected patients is not known at present.

The purpose of this study is to evaluate the efficacy of pegylated interferon in the treatment of chronic hepatitis B in HIV-infected individuals.

Apart from evaluating the efficacy of pegylated interferon therapy in this setting as such, i.e. in patients without present or future need of highly active antiretroviral therapy (HAART) for HIV-infection, there is a second purpose of this study, to investigate whether combination treatment of HBV-infection may be superior to pegylated interferon therapy alone.

Even though the generated data on standard interferon for the treatment of chronic HBV-infection in HIV-coinfected patients appears not promising at the moment, it is however the only treatment with a curative intention. Trials with pegylated interferon in the treatment of chronic HBV-infection in monoinfected patients with pegylated interferons showed higher efficacy than standard of care and when compared to historic data higher efficacy compared to non-pegylated interferon. This suggests in parallel a higher efficacy in the treatment of chronic hepatitis B in HIV-coinfected as well. At the same time, analysis suggested a further benefit when pegylated interferon therapy was prolonged beyond 24 weeks to 48 weeks as the elimination of HBV-DNA from serum appeared to continue beyond 24 weeks. Looking again at data from chronic hepatitis C infection, it is well known that the elimination kinetics of HCV-RNA in HIV-coinfected patients is slower compared to HCV-monoinfected patients, clearly suggesting rationale to offer 48 weeks pegylated interferon for the treatment of chronic hepatitis B to HIV-coinfected patients as well.

Parallel to the above said there are several other factors suggesting a positive effect of a combination treatment with nucleoside / nucleotide analogues active against HBV and interferon. Therefore patients in need for antiretroviral therapy with CD4-cells above 200/µl will be randomized to either PegIFN as part of a combination treatment with FTC and TDF or to FTC / TDF combination therapy alone. Patients receiving HAART will also receive a third active antiretroviral HIV-drug, either a non-nucleoside analogue (NNRTI) or a protease inhibitor (PI), at the choice of the investigator. A non-divergent antiretroviral therapy solely based on nucleoside analogues will not be allowed in this trial.

The objective of this study is to assess the efficacy (HBV-DNA < 5x10³ copies/ml, loss of HBe-Ag, HBe-seroconversion) and safety (adverse events, serious adverse events) of PegIFN for 48 weeks, to that of PegIFN for 48 weeks plus TDF and FTC containing HAART, to that of TDF and FTC containing HAART for 72 weeks.

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a liver biopsy within the last 12 months prior to screening consistent with chronic hepatitis B

Documented HIV-infection

CD4-cell count > 200 cells/µl

Elevated serum ALT > ULN but £ 10X ULN as determined by two abnormal values taken >14 days apart during the six months before the first dose of study drug with at least one of the determinations obtained during the screening period

Treatment with interleukin 2 or corticosteroids less than 6 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study.

Currently receiving investigational agents unless approved by the study coordinator

History of having received any systemic anti-neoplastic (including radiation < 6 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study.

Patients not receiving HAART (Arm A) must be expected not be in need for antiretroviral therapy for HIV-infection at any time during the study 72 weeks, as judged by the investigator.

Hypersensitivity to any of the components of the study drugs (tenofovir, emtricitabine, pegylated interferon alfa-2a)

Patients with a value of alpha-fetoprotein >100 ng/mL are excluded, unless stability (less than 10% increase) has been documented over at least the previous 3 months and magnetic resonance tomography of the liver shows no evidence of hepatocellular carcinoma.

Liver cirrhosis, CHILD-Pugh Score B or C; history or other evidence of bleeding from esophageal varices or other conditions consistent with decompensated liver disease

Alcohol abuse (> 30g ethanol/d for males, > 20 g ethanol/d for females) or use of other recreational drug substances)

Serum total bilirubin above twice the upper limit of normal

ALT > 10 times the upper limit of normal

Neurological / psychiatric disorders:

History of severe psychiatric conditions(ICD F30 - 33), graded by the consulting psychiatrist, in particular severe depression. Severe psychiatric disease is defined as major depression or psychosis, a period of treatment with an antidepressant medication or tranquilizer at therapeutic doses for depression or psychosis for at least 3 months, a suicidal attempt, hospitalization for psychiatric disease, or a period of disability due to a psychiatric disease.

History of a severe seizure disorder or current anticonvulsant use.

Cardiovascular disorders:

History or other evidence of chronic pulmonary disease associated with functional limitation.

Thyroid disease with thyroid function poorly controlled on prescribed medications. Patients with elevated thyroid stimulating hormone or T4 concentrations, with elevation of antibodies to thyroid peroxidase and any clinical manifestations of thyroid disease are excluded.

Other:

Gastrointestinal malabsorption

Evidence of an active or suspected cancer or a history of malignancy where the risk of recurrence is ³20% within 2 years. Patients with a lesion suspicious of hepatic malignancy on a screening imaging study will only be eligible if the likelihood of carcinoma is £10% following an appropriate evaluation.

History of organ transplantation

History or other evidence of severe retinopathy (e.g. CMV retinitis, macula degeneration) or clinically relevant ophthalmological disorder due to diabetes mellitus or hypertension